Sufficient lubricating tears are critical to good eye health. Because tears provide the same functions for the cornea of the eye that the blood provides for the body, any abnormalities in tear production can results in eye disorders. One such disorder is dry eye syndrome. Dry eye syndrome, commonly referred to as “dry eyes,” is a prevalent eye condition affecting approximately 20 million Americans. Specifically, dry eye syndrome is a disorder resulting generally from any abnormality in the tear production process, such as decreased tear production, excessive tear evaporation, or an abnormality in mucin or lipid component of the tear film that covers the normal ocular surface.
Although dry eye syndrome may have many different etiologies, the common denominator in all cases of dry eye is that it involves changes in the ocular surface due to alterations in the quality or quantity of tears. To understand the causes of dry eye syndrome, therefore, it is also important to understand the basics of tear production. The action of tears takes place in the three layers of the tear film. The mucin or mucus layer is the closest layer to the corneal epithelium. It is produced by the conjuctival goblet cells, and is absorbed by the corneal surface glycoproteins, creating a hydrophilic surface. Mucin deficiency, or mucopolysaccharide abnormalities, can lead to poor wetting or glycation of the corneal surface with subsequent desiccation and epithelial damage, even in the presence of adequate aqueous tear production. The aqueous layer, which floats on the mucin layer, is secreted by the lacrimal gland and incorporates all water-soluble components of the tear film. Further, the aqueous layer makes up 90% of the tear film's thickness. The significance of the aqueous layer is that it provides moisture and supplies oxygen and important nutrients to the cornea of the eye. Finally, on the outside of the aqueous layer is the lipid layer. The lipid or oil layer is produced by the meibomian glands with contributions from the glands of Zeis and Moll of the eye lids. The secretion of the lipid layer is an oily material, which is fluid at body temperature and retards the evaporation of the aqueous layer and lowers surface tension, thereby allowing the tear-film to adhere to the eye's surface. Androgen receptors are located in both the lacrimal and meibomian glands. A decrease in circulating androgen hormones can result in loss of the oil layer, which exacerbates the evaporative tear loss.
The ocular surface is bathed in tears that provide nutrients, lubrication, and information about chemical regulators to the cells of the corneal and conjunctiva. Tears are needed to maintain the normal ocular surface as well as to repair injury and surgical trauma. The blink reflex renews the tear film by delivering aqueous and lipid to the tear film and sweeping away debris. The normal blink interval is about 5 seconds under normal conditions. The tear film is typically stable for about 10 seconds. Tears are normally evaporated or forced out through the nasolacrimal ducts in the inner corner of the eyes on blinking.
Optimum ocular functioning requires essential fatty acids (EFAs). Because EFAs cannot be synthesized by the human body, they must be obtained from the diet. In particular, the omega-6 essential fatty acid, linoleic acid, is significant to dry eye syndrome. The body converts linoleic acid into series one prostaglandins (PGE1) by first converting it into gamma-linolenic acid (GLA), next into dihomo-gamma-linolenic acid, and finally into PGE1. PGE1 is important for lacrimal and salivary gland secretion and for T cell function. T cells are an essential element of the body's immune system, and the disruption of their functioning can contribute to the onset of diseases causing dry eye syndrome.
It is also important in the formation of PGE1 that the omega-6 essential fatty acids be in balance with omega-3 fatty acids. Omega-3 fatty acids help to prevent the metabolism of omega-6 fatty acids into pro-inflammatory compounds, thereby further enhancing the formation of PGE1. A disruption in this overall process is also believed to be an underlying cause of dry eye syndrome.
The typical symptoms of the dry eye syndrome include dryness, grittiness, irritation, difficulty reading for long periods of time, burning, and even the apparent contradiction of excessive tearing or watering. In extreme cases of dry eye, patients may become unusually sensitive to light, experience severe eye pain, and start to notice diminished vision. Successful treatment may be needed to avoid permanent damage.
These symptoms can result from many different causes of dry eye syndrome. Like most eye conditions, dry eye syndrome is often related to health conditions in the rest of the body, including dryness of other mucus membranes such as those located in the mount, vagina, and joints. Dry eye syndrome can also be a sign of digestive imbalances or of more serious systemic autoimmune diseases, such as rheumatoid arthritis, Sjogrens syndrome or lupus erthematosus. Other disorders, such as diabetes, glaucoma, thyroid disease, and blepharitis are also believed to be related to dry eye syndrome.
The causes of dry syndrome can be categorized based on which area or layer of the tear film is affected. Lubricant deficient dry eye encompasses disorders of the mucin layer and goblet cells. These disorders typically arise from vitamin A deficiency, protein malnutrition, conjunctival shrinkage, viral infections, thermal damage, irradiation damage, chemical injury, chemical preservatives, allergic conjunctivitis, and an increase in tear film osmolarity from lipid or aqueous dysfunction.
Aqueous tear-deficient dry eye encompasses disorders of the aqueous layer of the tear film. Tear deficient dry eye involves a decrease in the output of the lacrimal glands producing aqueous tears. This category can be further subdivided into Sjogrens-associated and non-Sjogrens-associated dry eye. Evidence exists that indicates that dry eye of both the Sjogrens and non-Sjogrens types has an inflammatory component that is an important feature in the pathogenesis of ocular surface disease. Sjogrens syndrome involves systems other than the eye including dry mouth, arthralgia, rheumatoid arthritis, and scleroderma. Non-Sjogrens aqueous deficiency, on the other hand, may be caused by age related atrophy of the lacrimal glands. The normal aging of tear glands, for example, can result in dryness, because tear volume decreases from age 18 as much as 60% by age 65. Further causes include isolated KCS, pharmaceuticals, menopause, noxious agents, damage to the lacrimal gland, and chronic viral infection.
Evaporative dry eye encompasses disorders of the lipid layer. Evaporative dry eye is characterized by excessive evaporative loss of tears from the ocular surface. The form most commonly encountered in clinical practice is meibomian gland dysfunction, which is characterized by a blockage of the mebomian glands and qualitative changes in the nature of their oily secretion. In normal eyes, lipids from the meibomian glands, and to a lesser extent the Moll and Zeiss glands, retard the evaporation of tears. Changes in the quality or quantity of tear lipids diminish the ability of the lipid layer to slow evaporation and maintain the integrity of the tear film. Both animal and human studies suggest that the pathogenesis of dysfunction of the lacrimal and meibomian glands may be linked. As is the case with aqueous tear-deficient dry eye, surface inflammation is a feature of evaporative dry eye and may play a role in both pathogenesis and symptomatology. Common causes for evaporative dry eye lipid layer disorders are aging, meibomianitis, and environmental conditions, such as the “sick office” syndrome, dry and/or windy climate, pollutants, and air conditioning. Computer use can also cause dry eye, as most people blink less frequently (about 7 times per minute vs. a normal rate of around 22 times/minute) that leads to increased evaporation along with fatigue and eye-strain associated with staring at a computer monitor.
It has now been clearly shown that a neural feedback mechanism links nerve endings on the ocular surface to the lacrimal glands. In response to neural stimulation, the lacrimal glands secrete a variety of components, including a number of small natural antibiotic proteins, like lactoferrin, an iron-binding protein released by neutrophils, and the neurotransmitter, acetylcholine which all play a significant role in controlling the turnover of epithelial cells on the corneal and conjunctival surfaces. The ocular surface nerve endings and the neural pathway are also important to the maintenance of a healthy ocular surface and the eye's ability to respond to injury.
Accordingly, the disruption of nerve endings on the ocular surface is also believed to cause dry eye syndrome. An example of this type of disruption occurs as a result of LASIK surgery. In LASIK surgery, up to 70% of the superficial corneal nerve endings are severed during flap creation. LASIK also introduces the following factors that can disrupt the sensory and autonomic neural connections that unify and drive the tightly integrated ocular surface/lacrimal/meibomian gland system: lid damage caused by the speculum, surgical induced fee radical production, decreased tear production, depressed corneal and conjunctival sensation, abnormal tear clearance, increase of inflammatory factors on ocular surface, and exacerbation of preoperative, possibly sub clinical, dry eye.
Inflammation of the ocular surface may also disturb the nerve endings, which in turn would disrupt the neural feedback mechanism and adversely affect tear production and cellular renewal. Sensation plays a critical role in initiating blink, as well. With compromised sensation, the blink rate can slow to the point where the tear film breaks up before the next blink can reconstitute it. The resultant absence of tear film will expose the epithelial surface to drying, mechanical damage, and the release of agonal chemicals from within the cells. This result initiates an inflammatory process. Even minimal levels of dry eye will result in a low-level ocular surface inflammatory component. If left untreated, smoldering inflammation can cause damage over time and increase susceptibility to bacterial conjunctivitis and viral conjunctivitis.
Most physicians recognize the underlying inflammatory process that is a part of dry eye in general and post-LASIK and other surgical induced dry eye. One cannot cut into tissue without causing the release of pro-inflammatory mediators and the diffusion of inflammatory cells to the incision. Proper blinking is necessary to distribute the top oily layer of the tear film. Surgery causes an alteration in the ability of the lid and tear film to protect the ocular surface. As a result, epithelial cells die at a greater rate and release chemicals, which cause damage and inflammation.
Additional causes of dry eye syndrome include the following. Extended use of contact lens can result in dry eye from corneal oxygen and nutrient deficiency. Protein build-up on contact lens can produce a breeding ground for bacterial growth and surface roughness, further contributing to inflammatory changes. Also, medications such as antibiotics, blood pressure medications, antidepressants, diuretics, over-the-counter vasoconstrictors, antihistamines, birth control pills, appetite suppressants, and ulcer medications, refractive surgery, autoimmune diseases and disorders such as those mentioned above, hormonal changes, and nutritional deficiencies can cause disruption in the tear production and retention process.
The conventional treatment for dry eyes involves treating the symptoms rather than the cause. For example, artificial tears and ocular lubricants are a common treatment. Although artificial tears may provide temporary relief, they merely palliate the symptoms. Furthermore, the preservatives used in the artificial tears can actually aggravate the condition, and can even kill corneal cells. Artificial tears that promise to “get the red out” actually reduce circulation in the eye by vessel constriction, decreasing production of the tear film, and worse, eventually make the eyes drier. The “rebound” dilation of surface vessels further contributes to the inflammatory response.
Another form of treatment is punctal occlusion. Punctal occlusion is a procedure used to help dry eye patients by closing the tear drainage canals with silicone plugs, which keep most of the fluid from draining away from the surface of the eye. This may provide long-term relief.
Thus far, there have been few approaches to the treatment of dry eye disorders that have been effective in addressing all the issues regarding dry eye syndrome. The present applicant previously developed a formulation, which is described in the specification of U.S. Pat. No. 6,506,412 and sold under the trademark HYDROEYE®, for treating the underlying inflammatory processes that cause dry eye syndrome. However, the HYDROEYE® treatment focused only on the production of the anti-inflammatory PGE1 and mucin. Although inflammation is still the main concern in dry eye syndrome, site-specific anti-inflammatory prostaglandins only address part of the dry eye inflammatory process. For example, the formulation did not address the inhibition of pro-inflammatory compounds, such as PGE2 and Interleukin-1. Further, the formulation did not address the inhibition of the growth of viral and bacterial pathogens in the three-layer tear film through the production of lactoferrin, which is a natural antibiotic.
Accordingly, there remains a need for an improved formulation that addresses a wider range of the underlying inflammatory processes that cause dry eye syndrome.